Chapter Four - New insights into the regulation of the actin cytoskeleton dynamics by GPCR/β-arrestin in cancer invasion and metastasis

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Abstract

Metastatic progression is strongly influenced by the connection between hyperactivated signaling pathways. G-protein coupled receptors (GPCRs) through β-arrestins (β-arrs), which serve as intracellular signaling molecules, integrate different pathways to control multiple aspects of metastatic process. As primary component of a core-scaffold, β-arr-dependent signaling represents a mean to direct spatiotemporal specificity of multi-protein complexes in invasion and extracellular matrix (ECM) degradation. Under this paradigm, β-arrs engage a growing number of signaling molecules and organizing protein networks controlling multiple pathways, and cytoskeleton modifications, permitting adaptation to the tumor microenvironment to sustain metastatic dissemination. These findings implicate GPCR/β-arr function as a regulatory tethering hub to orchestrate diverse cellular mechanisms of cancer cell migration and invasion that are critical for metastatic progression. In this chapter, we outline the most recent findings on GPCR/β-arr-guided molecular interactions in specific intracellular compartments to drive metastasis, while discussing new perspectives for the selection of most effective therapeutic options for a personalized medicine.

Introduction

Metastasis is a multistep process characterized by the dissemination of cancer cells from the primary tumor and colonization to distant organs, which include cell invasion in the surrounding tissues, intravasation into blood vessels and survival, followed by extravasation and/or re-growth at specific sites (Friedl and Wolf, 2010). To achieve metastatic re-growth a precise coordination of actin cytoskeleton dynamics, activation of downstream signaling pathways, and extracellular matrix (ECM) remodeling are essential to enable cancer cells to respond to external cues, and to define the complex invasive and metastatic potential of cancer cells (Friedl and Wolf, 2010; Lambert et al., 2017). A common feature of cell motility is the formation of long, force-supporting membrane protrusions, named based on their shape, such as filopodia, pseudopodia, and lamellipodia, which require F-actin polymerization, and are required by cells to extend forward, changing shape and adhere to their surroundings, followed by the contraction of the trailing end (Friedl and Wolf, 2010; Lambert et al., 2017). The primary driving force guiding cell movement is linked to tight regulation of actin assembly/disassembly at leading edge, operated by proteins involved in promoting the break of the existing actin filaments into smaller fragments to create a free barbed end, proteins nucleators facilitating association of actin monomers into filaments, and to formation of locomotory and invasive membrane protrusions. In particular, tumor cells use invasive protrusions called invadopodia to penetrate through the ECM and overcome surrounding matrix barriers (Eddy et al., 2017). Invadopodia are unique protrusions with matrix degrading activity formed specifically by invasive cancer cells, having a critical role in chemotaxis, migration and invasion, during metastatic process, containing a core of F-actin and specific proteins, such as cortactin and TKS5, at the leading edge of the invading cells where the secretory machinery and metalloproteases (MMPs) are located. The formation of invadopodia is a multistep process involving actin-binding proteins and signaling complexes, starting from invadopodia precursor formation before maturation to the degradation competent invadopodia (Eddy et al., 2017). Many findings indicate that the formation of invadopodia and its involvement in directional migration and chemotaxis is part of the epithelial-to-mesenchymal transition (EMT) process, and of the conversion of tumor cells into a migratory population, capable to degrade vascular basement membranes, and enter the blood stream, and of systemic metastasis (Eddy et al., 2017; Paterson and Courtneidge, 2018).

The spatial and temporal regulation of these processes is mediated by proteins interacting directly or indirectly with the actin and microtubule cytoskeleton elements, in proximity with signaling proteins to promote migration. In this regard, common signaling and cytoskeletal pathways used by both locomotory and invasive protrusions might be molecularly integrated by β-arrestins (β-arrs), scaffold proteins recognized for the precise control of spatiotemporal activation of signaling pathways in tumor cell motility. Here, we present the current understanding about the β-arr-dependent regulation of G-protein coupled receptors (GPCRs) signaling that modulates the metastatic progression.

Section snippets

Evolving roles of β-arrestin in GPCR regulation

GPCRs play an important role in cancer growth and progression, and represent one of the largest classes of surface receptors targeted by pharmacological drugs (Hauser et al., 2017; Lagerstrom and Schioth, 2008; Rosenbaum et al., 2009). The classic GPCR signaling paradigm has been that upon ligand-triggered GPCR activation, heterotrimeric αβγ G proteins, interacting with the intracellular loop that connects the transmembrane domains of GPCR, initiates a signal cascade as main transducers the

β-Arrestin-dependent signaling in cancer

GPCR field now encompasses an extensive knowledge that signals arising from different GPCR are linked to different malignancies, where β-arrs are expressed (Insel et al., 2018; Javadi et al., 2017; Nieto Gutierrez and McDonald, 2018; Peterson and Luttrell, 2017). For some GPCRs, β-arr can operate as an autonomous transducer of GPCR activation and might orchestrate GPCR signal across multiple cell locations (Eichel and von Zastrow, 2018). Most importantly, β-arr might be used by GPCR to overtake

β-arrs in GPCR-driven tumor cell migration and invasiveness

The ability of tumor cells to sense and migrate in response to external cues, including growth factor receptor signals, is a fundamental cellular behavior necessary for tumor invasion and metastasis. Although cell migration is not one single phenomenon, and tumor cells might operate different migratory phenotypes, this process is accomplished by changes in cell polarity and cytoskeletal rearrangement, cell detachment from, invasion through, and reattachment to their neighboring cells, and

c-Src/EGFR

The Src family of tyrosine kinases, including c-Src, c-Fgr, c-Fyn, c-Hck, and c-Yes, are considered key mediators of migratory signaling (Parsons and Parsons, 2004). The recruitment of c-Src to GPCR by β-arr represents one of the first evidence of a β-arr-mediated GPCR signaling, playing a key role in tumor cell motility, and metastatic behavior (Barlic et al., 2000; Luttrell et al., 1999). In the mode of RTK transactivation, occurring independently of ligand-binding, the interaction between

Cofilin

During cell migration, cells must modify actin filaments creating quickly new barbed ends also by uncapping and severing existing filaments, which are accomplished in part by the binding of different actin-bundling and cross-linking proteins (Blanchoin et al., 2014). Cofilin is one the most important proteins involved in the dynamic reorganization of actin cytoskeleton (Bravo-Cordero et al., 2013). The binding of cofilin to actin filaments results in filament severing, increasing the number of

Filamin-A

Among the well-known actin cross-linking proteins, filamin-A serves as a scaffold for many binding partners and represents a critical regulator of cell migration. Like β-arr, filamin-A can sequester different kinases at the leading edge and interacts with β-arrs downstream of angiotensin receptor (AT1AR) to regulate membrane ruffling and chemotaxis, suggesting that the interaction between these two proteins might reach a further level of actin dynamics during cancer cell motility (Scott et al.,

Small GTPases

Over 150 small GTPases are classified into five families: Ras/Ral/Rap, Rho/Rac/Cdc42, Rab, Arf, and Ran (Takai et al., 2001). Although the actin cytoskeleton reorganization is regulated by multiple factors, signaling platforms dependent by β-arr might regulate their GTP-dependent molecular switches, as scaffold of guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs) regulating their activity. Indeed, although β-arr

hMENA and other members of WASP family

The formation of a leading edge in migrating cells is linked to the assembly of a branched network of actin filaments, in which de novo actin filament polymerization is initiated by actin nucleators or nucleation complexes and the Arp2/3 complex, which are activated by nucleation-promoting factors of the Wiskott–Aldrich syndrome protein (WASP)/WASP-family, one of the three major classes of actin nucleators, cooperating with cofilin (Pollard and Borisy, 2003). A proteomic screen of

IQGAP1

The integrin-related protein IQ-domain GTPase-activating protein 1 (IQGAP1) is another important protein serving as an assembly scaffold for the organization of a multimolecular complex that would interface in the reorganization of the actin cytoskeleton at the plasma membrane (Smith et al., 2015; Watanabe et al., 2015). Emerging data suggest that the interactions between IQGAP1 and a plethora of interacting proteins might determine the formation of unique signalosome, providing spatio-temporal

Targeting the GPCR/β-arr system in cancer

The findings, demonstrating the critical role of GPCR/β-arr-driven signaling in rewiring the complex signaling network sustaining cancer progression, indicate that targeting GPCR/β-arr pathways might represent a new route of therapeutic intervention by using new strategies to hamper specifically β-arr-dependent network efficacy. The existence of biased ligands, which can transduce intracellular signaling from GPCR by favoring either the G-protein or the β-arr-mediated signaling pathways

Conclusions

The regulation of actin dynamic machinery is due by a complex signaling that enables malignant cells to invade the stroma, reach circulation and colonize distant sites, to regulate the metastatic process. The dialogue with the microenvironment in turn controls this complex signal network. Among these protein networks, GPCR/β-arr signals influence a large array of processes including metastatic process. Interest in GPCR/β-arr signaling was initially inspired by some relevant works on the role of

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC) to A.B. (AIRC IG 18382) and L.R. (AIRC IG 21372).

Acknowledgments

We gratefully acknowledge all members of the laboratory for their constant support and enthusiasm, and Maria Vincenza Sarcone for secretarial assistance.

References (134)

  • F.B. Gertler et al.

    Mena, a relative of VASP and Drosophila enabled, is implicated in the control of microfilament dynamics

    Cell

    (1996)
  • L. Girnita et al.

    {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase

    J. Biol. Chem.

    (2005)
  • L. Girnita et al.

    Beta-arrestin and Mdm2 mediate IGF-1 receptor stimulated ERK activation and cell cycle progression

    J. Biol. Chem.

    (2007)
  • C.G. Goertzen et al.

    KISS1R signalling promotes invadopodia formation in human breast cancer cell via β-arrestin2/ERK

    Cell. Signal.

    (2016)
  • C.Z. Hoeppner et al.

    Identification of a nuclear localization sequence in β-arrestin-1 and its functional implications

    J. Biol. Chem.

    (2012)
  • P.Y. Jean-Charles et al.

    Cellular roles of Beta-Arrestins as substrates and adaptors of ubiquitination and deubiquitination

    Prog. Mol. Biol. Transl. Sci.

    (2016)
  • J. Kang et al.

    A nuclear function of beta-arrestin1 in GPCR signalling: regulation of histone acetylation and gene transcription

    Cell

    (2005)
  • D. Keri et al.

    Reprogramming G protein coupled receptor structure and function

    Curr. Opin. Struct. Biol.

    (2018)
  • A.W. Lambert et al.

    Emerging biological principles of metastasis

    Cell

    (2017)
  • T. Lan et al.

    Downregulation of β-arrestin 1 suppresses glioblastoma cell malignant progression via inhibition of Src signalling

    Exp. Cell Res.

    (2017)
  • L.M. Luttrell et al.

    Translating in vitro ligand bias into in vivo efficacy

    Cell. Signal.

    (2018)
  • X. Ma et al.

    Acute activation of β2-adrenergic receptor regulates focal adhesions through βArrestin2- and p115RhoGEF protein-mediated activation of RhoA

    J. Biol. Chem.

    (2012)
  • X. Ma et al.

    β-Arrestin1 regulates the guanine nucleotide exchange factor RasGRF2 expression and the small GTPase Rac-mediated formation of membrane protrusion and cell motility

    J. Biol. Chem.

    (2014)
  • F.H. Marshall

    Visualizing GPCR ‘megaplexes’ which enable sustained intracellular signalling

    Trends Biochem. Sci.

    (2016)
  • W.E. Miller et al.

    Expanding roles for beta-arrestins as scaffolds and adapters in GPCR signalling and trafficking

    Curr. Opin. Cell Biol.

    (2001)
  • A. Nieto Gutierrez et al.

    GPCRs: emerging anti-cancer drug targets

    Cell. Signal.

    (2018)
  • N. Parisis et al.

    Pseudopodial and β-arrestin-interacting proteomes from migrating breast cancer cells upon PAR2 activation

    J. Proteomics

    (2013)
  • U. Philippar et al.

    A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis

    Dev. Cell

    (2008)
  • T.D. Pollard et al.

    Cellular motility driven by assembly and disassembly of actin filaments

    Cell

    (2003)
  • R. Ranjan et al.

    Novel structural insights into GPCR-β-arrestin interaction and signalling

    Trends Cell Biol.

    (2017)
  • M. Alemayehu et al.

    β-Arrestin2 regulates lysophosphatidic acid-induced human breast tumor cell migration and invasion via Rap1 and IQGAP1

    PLoS One

    (2013)
  • C.J. Alvarez et al.

    Obestatin stimulates Akt signalling in gastric cancer cells through beta-arrestin-mediated epidermal growth factor receptor transactivation

    Endocr. Relat. Cancer

    (2009)
  • D.A. Applewhite et al.

    Ena/VASP proteins have an anti-capping independent function in filopodia formation

    Mol. Biol. Cell

    (2007)
  • A. Bagnato et al.

    Endothelin-1 receptor drives invadopodia: exploiting how β-arrestin-1 guides the way

    Small GTPases

    (2016)
  • J. Barlic et al.

    Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI

    Nat. Immunol.

    (2000)
  • M. Bhattacharya et al.

    Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization

    Nat. Cell Biol.

    (2002)
  • L. Blanchoin et al.

    Actin dynamics, architecture, and mechanics in cell motility

    Physiol. Rev.

    (2014)
  • C. Bonnans et al.

    Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt signalling

    Proc. Natl. Acad. Sci. U. S. A.

    (2012)
  • J.J. Bravo-Cordero et al.

    Functions of cofilin in cell locomotion and invasion

    Nat. Rev. Mol. Cell Biol.

    (2013)
  • E. Bria et al.

    Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer

    Oncotarget

    (2014)
  • V. Bryja et al.

    Beta-arrestin is a necessary component of Wnt/beta-catenin signalling in vitro and in vivo

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • V. Bryja et al.

    Beta-arrestin and casein kinase 1/2 define distinct branches of non-canonical WNT signalling pathways

    EMBO Rep.

    (2008)
  • F.G. Buchanan et al.

    Role of beta-arrestin 1 in the metastatic progression of colorectal cancer

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • L. Chellini et al.

    Regulation of extracellular matrix degradation and metastatic spread by IQGAP1 through endothelin-1 receptor signalling in ovarian cancer

    Matrix Biol.

    (2018)
  • W. Chen et al.

    beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • R. Cianfrocca et al.

    Beta-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin-linked kinase

    Can. J. Physiol. Pharmacol.

    (2010)
  • R. Cianfrocca et al.

    Nuclear β-arrestin1 is a critical cofactor of hypoxia-inducible factor-1α signalling in endothelin-1-induced ovarian tumor progression

    Oncotarget

    (2016)
  • R. Cianfrocca et al.

    Blocking endothelin-1-receptor/β-catenin circuit sensitizes to chemotherapy in colorectal cancer

    Cell Death Differ.

    (2017)
  • P. Dasgupta et al.

    ARRB1-mediated regulation of E2F target genes in nicotine-induced growth of lung tumors

    J. Natl. Cancer Inst.

    (2011)
  • K. DeFea

    β-Arrestins and heterotrimeric G-proteins: collaborators and competitors in signal transduction

    Br. J. Pharmacol.

    (2008)

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